Methicillin-resistant Staphylococcus aureus (MRSA) are highly antibiotic resistant bacteria that either colonize or infect 1.8 million hospitalized patients in the United States each year. Upon discharge, these MRSA carriers incur a high risk for subsequent MRSA infection. In fact, one quarter of patients discharged harboring MRSA will develop inpatient and outpatient MRSA infections in the subsequent year. Besides incurring substantial morbidity and mortality, MRSA infections result in costly medical care, including frequent hospital readmissions. While prior studies have focused on preventing transmission, this proposal will fill the large and important gap of how to prevent infections in the growing number of people who already harbor MRSA. Identification of an effective strategy to reduce MRSA infection and hospitalization would be a major advancement in clinical care. The national burden of MRSA has led the Institute of Medicine to list the prevention of MRSA infection in the highest priority group (top quartile) for comparative effectiveness research. Project CLEAR - Changing Lives by Eradicating Antibiotic Resistance - is a randomized controlled clinical trial comparing serial decolonization versus standard-of-care education in patients harboring MRSA at hospital discharge. We hypothesize that serial decolonization of MRSA carriers with nasal mupirocin, oral chlorhexidine rinses, and chlorhexidine body wash will significantly reduce inpatient and outpatient MRSA infections in the 12 months following hospital discharge when compared to standard-of-care patient education on hygienic practices. While decolonization has been successful in short-term high risk areas, such as intensive care units, our trial will target the much larger arena of post-discharge infection and re-hospitalization. This large and important population has not been previously targeted for MRSA prevention. If our hypothesis is proven, post- discharge decolonization would become best practice for preventing MRSA infection in nearly two million hospitalized patients harboring MRSA in the United States alone. If disproven, findings will identify important factors, behaviors, and groups at highest risk for MRSA infection for further intervention efforts. Project CLEAR will evaluate the impact of decolonization in the general patient population as well as in Hispanic patients, in whom higher MRSA rates have been identified. Besides examining predictors of post- discharge infection, we will identify factors associated with unsuccessful decolonization. This will identify subgroups at particularly high risk for MRSA disease. Finally, we will assess the medical and non-medical costs associated with MRSA infection and quantify potential cost savings attributable to decolonization. MRSA containment and eradication is a national priority because of its virulence and rapid expansion in healthcare and community settings. This trial will provide a critically needed comprehensive evaluation of strategies to reduce MRSA infection risk across the continuum of inpatient and outpatient care. PUBLIC HEALTH RELEVANCE: This randomized controlled trial will compare strategies to reduce the risk of methicillin-resistant Staphylococcus aureus (MRSA) infection and re-hospitalization in MRSA carriers. This trial will provide critical answers about the role of decolonization versus standard-of-care education in preventing MRSA infections in the large group of high risk MRSA+ patients being discharged from hospitals. Findings could potentially impact best practice for the 1.8 million MRSA carriers who are discharged from U.S. hospitals each year.